Project Summary As the brain defines who we are, the consequences of a traumatic brain injury (TBI) can negatively impact all aspects of life for patients and their families. Approximately 75% of TBI are classified as mild TBI. After mild TBI, emerging data indicate that slow and progressive cell injury occurs throughout the brain triggering intrinsic self-repair mechanisms. For example, fibrosis, synaptic remodeling, axon sprouting and angiogenesis occur over the course of days and months after injury. This slow and protracted reorganization of neuronal circuits can promote recovery of function, but can also cause aberrant neuron firing that eventually culminates in the onset of post-traumatic epilepsy or stress, impairment of motor skills, mood and anxiety disorders. TBI also increases the risk of developing neurodegenerative diseases such as dementia and Parkinsonism. Unknown are the mechanisms underlying TBI-induced structural and functional changes as well as progressive neurodegeneration in the brain. In ongoing experiments, we have found a remarkable convergence between structural and functional organization of neuronal circuits and expression of Alpha2delta subunits of voltage gated calcium channels (VGCC). Alpha2delta subunits positively regulate synaptic transmission by increasing plasma membrane expression of VGCC. However, these subunits may also play a pathological role following injury. Accordingly, experiments in Aim 1 will use transcriptomic and genetic approaches combined with light- sheet microscopy and tissue optical clearing to explore the relationship between Alpha2delta1, maladaptive plasticity and progressive neurodegeneration after mild TBI. The primary goal is to identify post-injury changes in cortical circuits that could be manipulated for therapeutic gain. Manipulation of neural circuits is clinically feasible and can promote neurological recovery by affecting behavior in mammals. Aim 2 will explore the mechanism underlying Alpha2delta1-induced maladaptive plasticity and chronic neurodegeneration. Using genetic and viral approaches combined with physiology and behavior, we will test whether changes in Alpha2delta1 expression cause detrimental structural and functional alterations in the brain. Finally, this study seeks to examine whether it is possible to counteract these maladaptive changes by pharmacologically blocking Alpha2delta1 using clinically approved drugs. This proposal seeks to develop novel diagnostic tools and new ways to treat mild TBI pathophysiology as a disorder caused by a breakdown in brain homeostasis.